Contrast media may be administered in medical imaging procedures, for example X-ray, magnetic resonance and ultrasound imaging, to enhance the image contrast in images of a subject, generally a human or non-human animal body. The resulting enhanced contrast enables different organs, tissue types or body compartments to be more clearly observed or identified. In X-ray imaging, the contrast media function by modifying the X-ray absorption characteristics of the body sites into which they distribute.
Clearly however the utility of a material as a contrast medium is governed largely by its toxicity, by its diagnostic efficacy, by other adverse effects it may have on the subject to which it is administered, and by its ease of storage and ease of administration.
Since such media are conventionally used for diagnostic purposes rather than to achieve a direct therapeutic effect, when developing new contrast media there is a general desire to develop media having as little as possible an effect on the various biological mechanisms of the cells or the body as this will generally lead to lower animal toxicity and lower adverse clinical effects.
The toxicity and adverse biological effects of a contrast medium are contributed to by the components of the medium, e.g. the solvent or carrier as well as the contrast agent and its components (e.g. ions where it is ionic) and metabolites.
The following major contributing factors to contrast media toxicity and adverse effects have been identified:
the chemotoxicity of the contrast agent. PA1 the osmolality of the contrast medium, and PA1 the ionic composition (or lack thereof) of the contrast medium. PA1 --CONH--CH.sub.2 CH.sub.2 OH PA1 --CONH--CH.sub.2 CHOHCH.sub.2 OH PA1 --CONH--CH(CH.sub.2 OH).sub.2 PA1 --CON(CH.sub.2 OCH.sub.2 OH).sub.2 as well as other groups such as PA1 --CONH.sub.2 PA1 --CONHCH.sub.3 PA1 --OCOCH.sub.3 PA1 --N(COCH.sub.3)H PA1 --N(COCH.sub.3)C.sub.1-3 -alkyl PA1 --N(COCH.sub.3)-mono, bis or tris-hydroxy C.sub.1-4 -alkyl PA1 --N(COCH.sub.2 OH)-mono, bis or tris-hydroxy C.sub.1-4 -alkyl PA1 --N(COCH.sub.2 OH).sub.2 PA1 --CON(CH.sub.2 CHOHCH.sub.2 OH)(CH.sub.2 CH.sub.2 OH) PA1 --CONH--C(CH.sub.2 OH).sub.3 and PA1 --CONH--CH(CH.sub.2 OH)(CHOHCH.sub.2 OH). PA1 a bond, PA1 a O, S, N or C one atom chain, PA1 a NN, NC, NS, CC or CO two atom chain, PA1 or a NCN, OCN, CNC, OCO, NSN, CSN, COC, OCC or CCC three PA1 atom chain, PA1 an oxygen atom or a group NR.sup.1, CO, SO.sub.2 or CR.sub.2.sup.1 ; PA1 a group COCO, CONR.sup.1, COCR.sub.2.sup.1, SOCR.sub.2.sup.1, SO.sub.2 NR.sup.1, CR.sub.2.sup.1 CR.sub.2.sup.1, CR.sub.2.sup.1 NR.sup.1 or CR.sup.1.sub.2 O; PA1 a group NR.sup.1 CONR.sup.1, OCONR.sup.1, CONR.sup.1 CO, CONR.sup.1 CR.sup.1.sub.2, OCOO, CR.sup.1.sub.2 OCR.sup.1.sub.2, OCR.sup.1.sub.2 CO, CR.sup.1.sub.2 CONR.sup.1, CR.sup.1.sub.2 CR.sup.1.sub.2 CR.sup.1.sub.2, COCR.sup.1 R.sup.1 CO, CR.sup.1.sub.2 NR.sup.1 CR.sup.1.sub.2, CR.sup.1.sub.2 SO.sub.2 NR.sup.1, CR.sup.1.sub.2 OCO or NR.sup.1 SO.sub.2 NR.sup.1 ; PA1 where R.sup.1 is hydrogen or a C.sub.1-6 -alkyl or alkoxy group optionally substituted by hydroxy, alkoxy, oxa or oxo (e.g. a polyhydroxyalkyl, formyl, acetyl, hydroxyl, alkoxy or hydroxyalkoxy group) and where it is attached to a carbon atom R.sup.1 may also be a hydroxyl group. PA1 --NR.sup.1 COCONR.sup.1 -- PA1 --NR.sup.1 COCR.sup.1.sub.2 CONR.sup.1 -- PA1 --NR.sup.1 CR.sup.1.sub.2 CR.sup.1 OHCR.sup.1.sub.2 NR.sup.1 -- PA1 --CONR.sup.1 CR.sup.1.sub.2 CONR.sup.1 -- and PA1 --N(COR.sup.1)CR.sup.1.sub.2 CR.sup.1 OHN(COR.sup.1)--,
In coronary angiography, for example, injection into the circulatory system of contrast media has been associated with several serious effects on cardiac function. These effects are sufficiently severe as to place limitations on the use in angiography of certain contrast media.
In this procedure, for a short period of time a bolus of contrast medium rather than blood flows through the circulatory system and differences in the chemical and physicochemical nature of the contrast medium and the blood that it temporarily replaces can give rise to undesirable effects, e.g. arrhythmias, QT-prolongation, and, especially, reduction in cardiac contractile force and occurrence of ventricular fibrillation. There have been many investigations into these negative effects on cardiac function of infusion of contrast media into the circulatory system, e.g. during angiography, and means for reducing or eliminating these effects have been widely sought.
Early injectable ionic X-ray contrast agents, based on triiodophenylcarboxylate salts, were particularly associated with osmotoxic effects deriving from the hypertonicity of the contrast media injected.
This hypertonicity causes osmotic effects such as the draining out of water from red-blood cells, endothelial cells, and heart and blood vessel muscle cells. Loss of water makes red blood cells stiff and hypertonicity, chemotoxicity and non-optimal ionic make-up separately or together reduce the contractile force of the muscle cells and cause dilation of small blood vessels and a resultant decrease in blood pressure.
The osmotoxicity problem was addressed by the development of the non-ionic triiodophenyl monomers, such as iohexol, which allowed the same contrast effective iodine concentrations to be attained with greatly reduced attendant osmotoxicity effects.
The drive towards reduced osmotoxicity led in due course to the development of the non-ionic bis(triiodophenyl) dimers, such as iodixanol, which reduce osmotoxicity associated problems still further allowing contrast effective iodine concentrations to be achieved with hypotonic solutions.
This ability to achieve contrast effective iodine concentrations without taking solution osmolality up to isotonic levels (about 300 mOsm/kg H.sub.2 O) further enabled the contribution to toxicity of ionic imbalance to be addressed by the inclusion of various plasma cations, as discussed for example in WO-90/01194 and WO-91/13636 of Nycomed Imaging AS.
However X-ray contrast media, at commercial high iodine concentrations of about 300 mgI/mL have relatively high viscosities, ranging from about 15 to about 60 mPas at ambient temperature with the dimeric media generally being more viscous than the monomeric media. Such viscosities pose problems to the administrator of the contrast medium, requiring relatively large bore needles or high applied pressure, and are particularly pronounced in paediatric radiography and in radiographic techniques which require rapid, bolus administration, e.g. in angiography.
In practice, viscosities in excess of 30 mPas at body temperature (37.degree. C.) are unacceptably high for routine X-ray investigations, and especially for paediatric investigations. Accordingly, the maximum practical iodine concentration achievable with available non-ionic iodinated X-ray contrast agents is generally about 300-350 mgI/mL. Higher iodine concentrations, if accessible at acceptable viscosities, would increase the diagnostic efficacy of contrast enhanced images. Alternatively viewed, lower contrast medium viscosities for any given iodine concentration would increase ease of administration and the range of investigations and patients for which the contrast media could be used.